The overall goal of this research is to identify genes involved in the toxicity of beta-amyloid (Abeta), a peptide associated with Alzheimer's disease (AD). Abeta is toxic to cultured neuronal cells, but the molecular details of the response are largely unknown. Alterations in gene expression of cells upon the addition of Abeta will be analyzed by differential display technique, which is one of the specific aims of this proposal. In addition, cells surviving long-term exposure to the peptide become totally resistant to Abeta, reflecting the induction of protective genes and/or the inhibition of sensitive genes. Comparison of gene expression between Abeta- resistant and sensitive cells using differential display technique has revealed a number of candidate genes involved in Abeta protection. The second specific aim of this proposal is to examine these candidate genes for the relevance of their activation or inhibition to the Abeta resistance. It is hoped that the research will lead to the identification of new genes involved in Abeta toxicity which will then help to devise new therapeutic means to attack AD.